Gene Studies Confirm Autism's Complexity

The genetic basis of autism is so varied it may make more sense to speak of 'autisms,' three research teams suggested.

by Michael Smith Michael Smith North American Correspondent, MedPage Today
April 05, 2012

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The genetics of autism appear to be complicated and not based on a single gene mutation according to three studies of exomes, which is the DNA that codes for proteins, in people with autism.

Note that one of the studies estimated that if between 20% and 30% of the many mutations found were pathogenic, as many as 821 different genetic regions might be involved.

The genetic basis of autism is so complicated and varied, it may make more sense to speak of "autisms."

That's one of the implications of three independent studies, published online in Nature, that used broad analytic methods to look for small mutations that might be related to autism.

All three studies examined the exomes -- all the DNA that codes for proteins -- of people with autism, compared with parents and, in many cases, unaffected siblings.

They were looking for single nucleotide polymorphisms (SNPs), or single base pair changes in genes, that arose spontaneously during or near conception and therefore were not found in the parents.

While all three teams found many such "de novo" changes, only a few were in the same genes. In addition, few of the affected participants had the same changes, and there was little evidence of a pattern of variation that might explain the condition.

Indeed, "there are many 'autisms' represented under the current umbrella of (autism spectrum disorder)," argued one of the research groups, led by Evan Eichler, PhD, of the University of Washington in Seattle.

Eichler and colleagues estimated that if between 20% and 30% of the many mutations they found were pathogenic, as many as 821 different genetic regions might be involved.

And another group, led by Matthew State, MD, PhD, of Yale University, argued that their findings support the notion that "hundreds of genes or more" might be involved.

On the other hand, it's unlikely that individual SNPs in hundreds of genes play a major role in autism, according to the third group, led by Mark Daly, PhD, of Massachusetts General Hospital in Boston.

Instead, they argued, the data suggest at best a modest role for any such mutation and "importantly, a single deleterious event is unlikely to fully explain disease in a patient."

On the other hand, the research teams said they had pinned down a few genes where the effect appears to be greater, including some that had not previously been linked to autism.

The work follows a major report in 2010 that showed that inherited copy number variations -- insertions or deletions of regions of DNA -- play a role in autism spectrum disorder.

But, like the current studies, that report also found that few people with autism have the same pattern of insertions or deletions.

The current studies "represent a significant effort," commented Stephen Scherer, PhD, of the Hospital for Sick Children in Toronto, who led the earlier work.

It's interesting, Scherer told MedPage Today in an email, that the putative susceptibility genes found in the three studies "are mostly different than those loci identified in (copy number variation) data."

And Scherer cautioned that any clinical implications of the analyses will need to wait on more research, perhaps using whole genome analysis methods, in larger cohorts.

In a comment posted on the National Institute of Mental Health website, institute director Thomas Insel, MD, argued that studying de novo mutations is "tough sailing because there are so many of these changes in all of us and most of these single base changes have no impact."

But the studies confirm that "genetic risk is both complex and substantial," Insel said. And they imply that what's important in these sorts of spontaneous mutations is their location in the genome, rather than the number, he added.

The types of mutations under study occur in the sperm and ova, but the researchers found that they are much more likely to come from the father's side of the equation.

For instance, in an analysis of 51 such variants, Eichler and colleagues found a 4:1 bias in favor of paternal mutations, a finding that was significant at P<1.4x10-5.

Moreover, the number of such de novo mutations was positively correlated with increasing paternal age, they reported.

Insel argued that the findings might provide a link between environmental and genetic explanations of autism -- as the father's age increases, environmental factors may have an increasing chance to cause spontaneous changes in the DNA of his sperm, some of which might be harmful.

The three teams did identify several genes, including CHD8, NTNG1, GRIN2B, LAMC3, SCN1A, and SCN2A, in which the de novo mutations caused changes in the gene product that might play a role in susceptibility to autism.

While most de novo mutations have no effect, State and colleagues reported that participants with autism had significantly more variants with an effect (at P=0.01) than did their unaffected siblings.

Put another way, the odds ratio of active to "silent" mutations in people with autism or their siblings was 1.93, which was significant at P=0.02.

When State and colleagues restricted their analysis to genes expressed in the brain, the effect was even greater: The odds ratio of active to silent mutations was 5.65 (95% CI 1.44 to 22.2), which was also significant at P=0.01.

They estimated that as many as 14% of affected individuals have such a risk variant, which would be in addition to those who have copy number variants or one of the identified genetic syndromes.

Eichler and colleagues analyzed a list of 126 gene variants that caused altered proteins, and a map of the interactions of those genes showed that 49 of them (39%) were part of a single network involved in brain signaling.

The study by State and colleagues, and the study by Eichler and colleagues, were supported by the Simons Foundation.

The study by Daly and colleagues was supported by the NIH.

The journal said all of the authors declared they had no competing interests.

Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, RN, BC-ADM, Nurse Planner

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